Program Director/Principal Investigator: Schryvers, Anthony B.ABSTRACTNeisseria gonorrhoeae, the bacterial pathogen that causes gonorrhea, is now considered an ?Urgent Threat?due to the recent emergence of strains with multi-drug resistance to the antibiotics that are frequently usedduring treatment. Due to the emergence of these `superbug' strains, we are progressing towards the spread ofuntreatable gonococcal infections. This situation has added to the urgency for developing a vaccine to preventthese infections, as untreated gonococcal infections can lead to pelvic inflammatory disease, ectopicpregnancy, infertility and invasive infections. Development of a gonococcal vaccine has been challenging dueto the remarkable ability of the bacterium to vary its surface components and suppress the development of aprotective immune response against reinfection in humans, and due to the lack of appropriate animal modelsavailable to study infection and immunity of this pathogen. The primary focus of this proposal is to furtherdevelop a protein-based vaccine that targets the constitutively-expressed gonococcal transferrin bindingprotein B (TbpB), which captures iron from human transferrin. It is an ideal target since the transferrin receptorin N. gonorrhoeae is required for survival on the mucosa and we have shown that it is capable of reducingcolonization in a mouse model. We have demonstrated that transferrin-binding defective mutants of TbpBinduce a more protective immune response than the wild type proteins, and are currently finalizing theantigenic composition of our TbpB-based vaccine. In this project, we will scale-up and optimize production andpurification of our antigens, develop an optimal vaccine formulation and perform all the steps required forimplementing Phase I trials in humans. Cross-protection will be evaluated in a lower genital tract colonizationmodel and a model of pelvic inflammatory disease using female transgenic mice expressing human CEACAMreceptors and human transferrin, which facilitate gonococcal mucosal attachment and growth, respectively.Together with an industrial sponsor, Vaxiron, Inc., we will develop quality control tools and metrics forassessing vaccine antigen formulations, transfer production of our vaccine formulation to a contractmanufacturing organization, complete all the quality, stability and toxicology studies required for regulatoryapproval to proceed to a future Phase I clinical trial after the culmination of this project.